1. Field of the Invention
This invention relates to 4H-pyrimido[2,1-a]isoquinoline derivatives and to their use as inhibitors of allergic reactions.
2. Description of the Prior Art
Various medicinal agents have been employed in the treatment of allergic reactions such as bronchial asthma and allergic rhinitis which are believed to result mainly from antigen-antibody interaction. With respect to bronchial asthma, one of the most serious of these allergically-mediated diseases, bronchodilators such as theophylline, isoproterenol, epinephrine and atropine are used primarily in providing symptomatic relief. These agents, however, have undesirable side effects, e.g. cardiac stimulation and gastrointestinal distress.
With the recent introduction of disodium cromoglycate described by J. S. G. Cox, et al. in Adv. in Drug Res., 5, 115-116 (1970), the physician has been provided with an agent which, when administered to asthmatic patients prior to inhalation of specific antigens, inhibits the release of mediators, e.g. histamine and SRS-A (slow-reacting-substance of anaphylaxis), believed to be responsible for the asthmatic response. While making possible a prophylactic treatment for bronchial asthma without cardiovascular side effects and thus representing a significant advance, disodium cromoglycate suffers from a major disadvantage in that it is not orally absorbed and must be administered by inhalation.
No examples of the pyrimido[2,1-a]isoquinoline derivatives of the present invention have been found in the literature. The following references illustrate structurally related compounds known in the art.
1. H. Reimlinger et al. in Chem. Ber., 105, 108 (1972) describe the synthesis of several 4-oxo-4H-pyrimido[2,1-a]isoquinolines (formula A below) as well as some isomeric 2-oxo-2H-pyrimido[2,1-a]isoquinolines (formula B below). ##STR1## R = H, CH.sub.3, C.sub.6 H.sub.5 R.sup.1 = H, C.sub.6 H.sub.5 ##STR2## R = H, CH.sub.3, C.sub.6 H.sub.5
2. U.S. Pat. No. 3,792,050 discloses 2-oxo-2H pyrimido[2,1-a]isoquinolines of the formula ##STR3## where the dotted line represents an optional double bond. The compounds of formula C are reported to have anti-inflammatory activity.
3. U.K. Pat. No. 1,451,423 discloses 1-oxo-1H-6-substituted pyrimido[1,2-a]quinoline-2-carboxylic acids (and salts and esters thereof) of the formula ##STR4## where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each hydrogen, fluorine, chlorine, bromine, lower alkyl, lower alkoxy, carbo(lower)alkoxy, methylthio or methylsulphinyl or R.sup.2 and R.sup.3 taken together are 1,3-butadienyl, methylenedioxy or ethylenedioxy and R.sup.6 is chlorine, bromine, hydroxy, lower alkoxy, alkenyloxy or alkynyloxy. The disclosed compounds D are said to possess antiallergy activity. Tetrazolyl amide derivatives of the above compounds (see formula E below) are disclosed in U.S. Pat. No. 4,017,625 as antiallergy compounds. ##STR5## R.sup.1 /R.sup.2 = hydrogen, lower alkyl, lower alkoxy, fluoro or chloro R.sup.3 = chloro, bromo or lower alkoxy
R.sup.1 and R.sup.2 when taken together may be alkylenedioxy.
4. U.S. Pat. No. 3,847,919 discloses a series of 1,2,3-triazolo[4',5':4,5]pyrimido[2,1-a]isoquinolin-8-ones of the formula ##STR6## where R.sup.1 is hydrogen or an alkyl, alkoxy or benzyl substituent in the 1-, 2-, 3-, 4- or 5-position. The compounds of formula F are indicated as having antiallergy activity.